Citrate-Based Dialysate Chemical Formulations

ABSTRACT

The present invention constitutes dialysate formulations that are suitable for use in preparing dialysate solutions for use in batch and/or proportioning systems and for improving dialysis efficiency by reducing or preventing clotting of the dialysis flow paths. The dialysate chemical formulations for one batch of dialysate comprise an acid concentrate stored in a first vessel, and a citrate-containing bicarbonate concentrate stored in a second vessel. The contents of the first and second vessels are emptied into a dialysate preparation tank and mixed with water to form a batch quantity of dialysate solution. Alternately, a dry acid and/or a dry citrate-containing base concentrates are dissolved separately in measured quantities of water to form liquid concentrates which are then used in conjunction with a proportioning machine to generate on-line a final dialysis solution stream.

BACKGROUND OF THE INVENTION

A. Field of the invention

This invention relates generally to chemical formulations that are usedfor the preparation of dialysate solutions, and more particularly to thedistribution of chemicals into two dialysate concentrate formulationsthat are particularly suitable for use in preparing dialysate in bothbatch and proportioning dialysis systems. In the present context, theterm “batch” refers to the quantity of dialysate constituents, that whenmixed with the proper amount of water, forms enough dialysate solutionsufficient for one complete dialysis session for single or multiplepatients. The term “proportioning” refers to the traditional types ofmetering systems that are used to prepare dialysate, namely fixed-volumeand dynamic proportioning systems. The two dialysate concentrateformulations are generally suitable for both batch preparation andon-line generation of dialysate as in traditional proportioning meteringsystem after powder concentrate is dissolved to make a liquidconcentrate.

B. Statement of Related Art

Kidneys help the body maintain a normal internal environment calledhomeostasis by ridding the body of excess fluids and metabolic wasteproducts (toxins) as well as maintaining precise levels of glucose andelectrolytes. When a person's kidneys fail because of disease ortraumatic removal, excess fluid and toxic waste (uremic poisoning)accumulate in that person's body. This uremic poisoning eventuallycauses death unless the waste material is removed by some artificialmeans. Dialysis, including hemodialysis and peritoneal dialysis, is atreatment for patients that suffer from kidney failure. In hemodialysis,blood is pumped from the patient's body through an extracorporealartificial kidney circuit, where blood-borne toxins and excess water arefiltered out of the blood through a semipermeable dialyzer membrane intoan electrolyte and plasma-resembling medium (i.e., dialysate). Inperitoneal dialysis, the patient infuses a quantity of dialysate intothe peritoneal cavity, and the peritoneal membrane acts as thesemipermeable membrane. After a dwell period, the dialysate fluid isdrained and a fresh supply of peritoneal dialysate is added to theperitoneal cavity.

A variety of concentrate formulations for preparing dialysis solutionsused in hemodialysis or in peritoneal dialysis are known. See, forinstance, U.S. Pat. Nos. 4,336,881; 4,489,535; and 4,756,838. Theseformulations vary not only with respect to specific constituents, butalso with respect to the concentrations of these constituents.Generally, concentrate formulations include sodium chloride as the majorconstituent and potassium chloride, calcium chloride and magnesiumchloride as minor constituents. If required by the patient, dextrose mayalso be included. Sodium acetate and/or sodium bicarbonate are alsoincluded as a buffer source to correct for metabolic acidosis. Withacetate buffer, all of the constituents can be combined into a singleconcentrate. With bicarbonate buffer, two concentrates are necessary toprevent the precipitation of calcium and magnesium as carbonate salts.

Conventional two-part bicarbonate-based dialysis solutions are preparedby mixing an “acid” concentrate, a “base” (i.e., bicarbonate)concentrate and water. Normally the acid concentrate includes all of theacid (e.g., acetic acid), dextrose, calcium, magnesium, potassium andsome portion of the physiologic requirement for sodium chloride whereasthe base concentrate includes sodium bicarbonate and the balance of therequired sodium chloride. In some commercial formulations of dialysateconcentrates, the sodium chloride content of the base concentrate iszero. Since acetic acid is a liquid at room temperature, most of theacid concentrates using acetic acid are liquid products; whereas thebase concentrates are produced both as powder and liquid concentrates.Many other combinations of acid and base concentrates that arecommercially available are specific to the dialysis solution preparationmethods and delivery equipment. For instance, the Aksys PHD® dialysissystem (available from Aksys, Ltd., Lincolnshire, Ill., USA) uses aliquid acid concentrate and a dry base concentrate housed in twoseparate vessels. The sequential mixing of the two concentrates withpurified water generates carbonic acid as reaction product of the acidwith bicarbonate and results in a final dialysate having a pH withinphysiological limits but with sufficient acidity to prevent calcium andmagnesium carbonate precipitation.

As noted above, kidney failure patients accumulate excess fluids andwaste products in their body such as blood urea nitrogen (BUN) andcreatinine. In fact, the reduction in blood level concentrations ofthese two substances is generally used to gauge the efficiency andoverall effectiveness of dialysis. Often the efficiency of dialysis canbe compromised by a number of factors, one of which is the blockage ofdialyzer blood flow path by blood clots. Several attempts have been madeto prevent or reduce clotting of dialyzer blood flow paths. Forinstance, Ward et al. U.S. Pat. No. 5,032,615 described the use ofextra-corporeal infusion of anti-coagulants during dialysis. Ahmad etal. U.S. Pat. No. 5,252,213, issued Oct. 12, 1993, described the use ofanti-coagulants in the dialysate formulations. The methods described inthe patents of Ward et al. and Ahmad et al. require complicatedmonitoring or regulating systems to control the delivery of theanti-coagulants during dialysis or the use of chemical formulations thatare inherently unstable and thus cannot be stored for prolonged timeperiods, respectively.

A number of dialysate delivery systems are available for preparing anddelivering dialysate. Traditionally, dialysis systems were used for thepreparation of large batches (e.g., 120 L or more) of dialysate. Singlebatches were prepared by adding dialysate constituents to a batch tankwith a predetermined amount of purified water and mixing untildissolution occurred to yield a dialysate having a final desiredconcentration. A reference describing the preparation of a largequantity of dialysate off-line in 50 liter carboys in a factory-likefacility is S. T. Boen et al., Periodic Peritoneal Dialysis Using TheRepeated Puncture Technique And An Automatic Cycling Machine, Vol. XTrans. Amer. Soc. Artif. Int. Organs, 44.409-414 (1964).

The two types of dialysis proportioning systems that are currently usedto prepare dialysate include fixed-volume proportioning and dynamic (orservo-controlled) systems. For fixed-volume proportioning systems, fixedvolumes of concentrate and water are mixed to form the final dialysate.Two pumps are used to dispense acid and bicarbonate concentrates while athird pump is used to meter water. The composition of the finaldialysate is monitored by a conductivity sensor. Dynamic proportioningsystems rely on conductivity monitoring to adjust the amount of acid andbase concentrates that is mixed with water to yield a dialysate having apre-set conductivity. These systems generally employ a second set ofconductivity sensors for safety monitoring. The different approaches topreparing bicarbonate-containing dialysate resulted in a variety ofproportioning ratios for the acid concentrates, base concentrates andwater. Each proportioning ratio requires a particular set of acid andbase concentrates. Some dialysis machines are designed for use with asingle proportioning ratio while other machines use differentproportioning ratios.

With the advent of on-line proportioning systems, dialysates can beprepared continuously on-line by combining water, which has been firstpurified by a separate water treatment system, with liquid concentratesof the dialysate constituents using a proportioning pump. Arepresentative patent discussing this technique is the patent toSerfass, U.S. Pat. No. 3,441,135. An Association for the Advancement ofMedical Instrumentation publication AAMI RD61:2000 describes four suchproportioning systems where liquid acid concentrates and liquidbicarbonate concentrates are mixed on line with water to produce a finaldialysate for use with hemodialysis therapy. These mix ratios aregenerally known as 35X, 36.83X, 45X and 36.1X. The details of differentproportions are listed in Table 1(b). Recent advancements in automationtechnology and frequent on-line quality measurements have made itpossible for use of proportioning systems in a home setting. Newtechnology have made it possible to overcome the drawbacks of aproportioning systems and offer a more compact design particularlysuitable for the home setting.

It is therefore an object of the invention to provide for the improvedconcentrate formulations of dialysate constituents that are suitable forpreparation of batch as well as on-line generation of dialysate. Thisapproach increases the efficiency of dialysis treatment by reducingclotting of blood. It is a further object of the invention to providedialysate concentrate formulations that are particularly suited forautomatic mixing of the constituents in a dialysate or concentrate tank.A further object of the invention is to provide concentrate formulationsthat assure patient safety, that are storage stable and will withstandtemperature extremes when the concentrates are shipped from the locationwhere they are formulated and bottled to the eventual destination.

SUMMARY OF THE INVENTION

The present invention relates to citrate-based dialysate formulationsthat are suitable for use in preparing on-line approach or batchquantities of dialysate, concentrate solutions, and kits and methodsemploying the same. The dialysate chemical formulations comprise aliquid or dry acid concentrate unit stored in a first vessel, and aliquid or dry citrate-containing bicarbonate concentrate unit stored ina second vessel. The contents of the first and second vessels areemptied into a dialysate preparation tank and mixed with water to form abatch quantity of dialysate solution. Alternately, the contents of thevessels can be proportioned into a water stream for on-line generationof a dialysate solution. The mixing of chemicals and dilution with wateris accomplished in an enclosed environment, under small pressure suchthat carbon dioxide formed remains dissolved in the solution. Thepresent invention relates specifically to the dialysate chemicalformulations; the vessels containing the chemicals and the machine thatprepares the solution are not considered a part of the present inventionper se.

In one embodiment of the invention, a dry citrate-containing baseconcentrate is provided. The dry citrate-containing base concentratecomprises citrate, bicarbonate and a salt, wherein the base concentrateupon mixing with an acid concentrate and a prescribed volume of waterforms a final volume of a dialysis solution.

In one aspect of this embodiment of the invention, the dry baseconcentrate comprises: (a) bicarbonate in an amount sufficient toprovide, in the final dialysate, concentration ranging from about 15 to50 mEq/L; (b) sodium in an amount sufficient to provide, in the finaldialysate, a concentration ranging from about 125 to 150 mEq/L; (c)chloride in an amount sufficient to provide, in the final dialysate, aconcentration ranging from about 80 to 130 mEq/L; and (d) citrate in anamount sufficient to provide, in the final dialysate, a concentrationranging from about 1 to 8 mEq/L, wherein the base concentrate uponmixing with an acid concentrate and a prescribed volume of water forms afinal volume of a dialysis solution.

In another aspect of this embodiment of the invention, the baseconcentrate comprises sodium bicarbonate; sodium citrate; and sodiumchloride, wherein the sodium bicarbonate and sodium citrate are presentin molar ratios ranging from 50:1 to 15:8 and wherein sodium chloride ispresent in an amount sufficient to provide a sodium concentrationranging from 125 to 0.150 mEq/L in a final dialysate solution when thebase concentrate and an acid concentrate are mixed in a prescribedvolume of water.

In another embodiment of the invention, a kit is provided for preparinga dialysis solution. The kit comprises: (a) a container of a basecomponent comprising a citrate, a bicarbonate and a salt; and (b) acontainer of an acid component comprising an acid selected from thegroup consisting of acetic acid, citric acid, sodium diacetate andlactic acid, wherein the addition of base concentrate and acidconcentrate to a prescribed volume of water produces a final volume of adialysis solution. Presently preferred formulations for the liquid acidconcentrate and dry bicarbonate units are set forth in Tables 5 and 6,respectfully.

In another embodiment of the invention, a method is provided for makinga dialysis solution. The method comprises: (a) providing a baseconcentrate comprising a citrate, bicarbonate and a salt; (b) providingan acid concentrate comprising an acid selected from the groupconsisting of acetic acid, citric acid, sodium diacetate and lacticacid; and (c) adding the base concentrate and said acid concentrate to aprescribed volume of water so as to produce said dialysis solution.

In another embodiment of the invention, a method is provided for makinga dialysis solution. The method comprises: (a) providing a baseconcentrate comprising a citrate, bicarbonate and a salt; (b) providingan acid concentrate comprising an acid selected from the groupconsisting of acetic acid, citric acid, sodium diacetate and lacticacid; and (c) adding the base concentrate and said acid concentrate to aprescribed volume of water so as to produce said dialysis solution on abatch basis.

In one aspect of this embodiment of the invention, the base concentrateand acid concentrate are separately dissolved into water to form baseand acid solutions. The base and acid solutions are then metered into ametered volume of water so as to produce said dialysis solution on-lineon a continuous basis. The dissolution of the base and/or acidconcentrates into water is necessary if the base and/or acidconcentrates are in dry powder form.

These and other embodiments of the invention will become apparent inlight of the detailed description below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The assignee of the present invention has developed a daily hemodialysismachine that is particularly suitable for use in the home, nursing home,and limited care environment. The machine is described in the patent ofKenley et al., U.S. Pat. No. 5,591,344, issued Jan. 7, 1997, and isincorporated by reference herein. The machine prepares the dialysatesolution a batch at a time, just prior to the start of the dialysissession. The dialysis chemicals are shipped to the machine site invessels, each of which contains the batch quantity of either powdered orliquid dialysate chemicals. Thus, in one embodiment of the invention,the dialysate chemicals are used in conjunction with the machinedescribed in the above Kenley et al. patent. A particularly preferredmachine is the Aksys PHD® batch dialysis system which is commerciallyavailable from Aksys Ltd. The PHD® has been approved in the UnitedStates and in Europe for use in the home environment by dialysispatients.

To prepare the dialysate solution, dry dialysate chemicals in one batchquantity vessel, and liquid dialysate chemicals from one batch quantityvessel are dispersed into the dialysate tank. This process is describedin detail in the above-referenced Kenley et al. patent.

In another embodiment of the invention, the dialysate chemicals are usedin a dialysate proportioning system such as a fixed-volume or dynamicproportioning system.

The present invention contemplates dialysate concentrate formulationsfor preparing bicarbonate-based dialysate, consisting of a bicarbonateconcentrate containing citrate and an acid concentrate which are storedin separate containers or vessels and mixed together in a dialysatesuitable for hemodialysis or for peritoneal dialysis. The acidconcentrates and bicarbonate concentrates of the invention are speciallyformulated to allow a physician to selectively tailor a dialysateformulation to a patient's particular health needs and to allow apatient to easily prepare batch size quantities of dialysate using ahome dialysis machine described in Kenley et al. patent. The finaldialysate preferably includes the following constituents (Table 1(a))and is prepared in the following proportions (Table 1(b)):

TABLE 1(a) Formulations Table for Final Dialysate for all HD and PDSolutions Constituent Low High Units Sodium 125 150 mEq/L Bicarbonate 1550 mEq/L Citrate 1 8 mEq/L Potassium 0 5 mEq/L Magnesium 0 3 mEq/LCalcium 0 5 mEq/L Dextrose 0 4250 mg/dL Chloride 80 130 mEq/L Acetate 08 mEq/L Lactate 0 50 mEq/L NB: HD = hemodialysis. PD = peritonealdialysis.

TABLE 1(b) Volume and ratio ranges for dialysis components ConstituentLow High Units Comment Acid Mix Ratio—Acid 1:34  1:136 n/a For AksysBatch system (1:136) Concentrate and the sum of and other proportioningsystems Base Concentrate and water (1:34, 1:35.83, 1:44, 1:35.1).Bicarbonate Mix ration— 1:19.1 1:136 n/a For Aksys Batch system(1:136Base Concentrate and the for dry powder mixed directly) sum of AcidConcentrate and and other proportioning systems water (1:27.6, 1:19.1,1:25.1, 1:31.8). Diluted Dialysate Solution  1  240 liters For AksysBatch system and Batch Size for a single other proportioning systemstreatment utilizing batch mixing of powder concentrates Diluted dialysissolution for 50 1500 mL/min For most commercial proportioning systemsproportioning systems

The acid concentrate of the invention includes sodium chloride, dextroseand minor amounts of chloride salts of potassium, calcium and magnesiumand an acid such as acetic acid, citric acid, sodium diacetate(CH₃CO₂Na. CH₃CO₂H; CAS #000126-96-5), lactic acid or any other acid.Additionally, the corresponding salts of acetic acid (acetate), citricacid (citrate) or lactic acid (lactate) may be used.

As used herein, “chloride” refers to anionic chloride. Thus, the term“chloride” includes anionic chloride and the salt forms thereof, such asmay be formed from chloride anion(s) and physiologically-acceptablecation(s). The term “chloride” is not intended to include compoundswherein the chloride atom is covalently bonded to, for example, a carbonatom in an organic molecule. Exemplary physiologically-acceptablecations include, without limitation, hydrogen ions (i.e., protons),metal cations, and ammonium cations. Metal cations are generallypreferred, where suitable metal cations include, but are not limited to,the cationic forms of sodium, potassium, magnesium and calcium. Ofthese, sodium and potassium are preferred, and sodium is more preferred.A composition containing chloride salts may contain a mixture ofphysiologically-acceptable cations. A suitable chloride source may beany of hydrochloric acid, sodium chloride, potassium chloride, calciumchloride, magnesium chloride, ammonium chloride, or the like. In thepreferred embodiment, chloride is in the form of sodium chloride.

As used herein, “acetate” refers to an acetate anion, in any form,including acetic acid and salts of acetic acid. Acetate is an organic,monocarboxylate with the formula Hz CCO₂ ⁻. The acetate salt is composedof one or more acetate anions in association with one or morephysiologically-acceptable cations. Exemplary physiologically-acceptablecations include, but are not limited to, protons, ammonium cations andmetal cations, where metal cations are preferred. Suitable metal cationsinclude, but are not limited to, sodium, potassium, magnesium andcalcium, where sodium and potassium are preferred, and sodium is morepreferred. For instance, the acetate source may be any of acetic acid,sodium acetate, sodium acetate trihydrate, sodium diacetate, potassiumacetate, calcium acetate, calcium acetate monohydrate, magnesiumacetate, magnesium acetate tetrahydrate, and the like.

Exemplary acetate compounds of the present invention include, but arenot limited to, acetic acid, sodium acetate, sodium diacetate, sodiumacetate trihydrate, potassium acetate, calcium acetate, calcium acetatemonohydrate, magnesium acetate, and; magnesium acetate tetrahydrate. Inthe preferred embodiment, the acetate of the acid concentratecomposition is present as acetic acid or sodium diacetate.

As used herein, “lactate” refers to a lactate anion, in any form,including lactic acid and salts of lactic acid. Lactate is an organic,monocarboxylate with the formula H₃ CCH(OH)CO₂ ⁻. A lactate salt iscomposed of one or more lactate anions in association with one or morephysiologically-acceptable cations. Exemplary physiologically-acceptablecations include, but are not limited to, protons, ammonium cations andmetal cations, where metal cations are preferred. Suitable metal cationsinclude, but are not limited to, sodium, potassium, magnesium andcalcium, where sodium and potassium are preferred, and sodium is morepreferred.

Exemplary lactate compounds of the present invention include, but arenot limited to, lactic acid, sodium lactate, potassium lactate, calciumlactate and magnesium lactate trihydrate. In one embodiment, the lactateof the acid concentrate composition is present in the form of lacticacid.

As used herein, “mEq/L” refers to the concentration of a particulardialysate component (solute) present in proportion to the amount ofwater present. More specifically, mEq/L refers to the number ofmilli-equivalents of solute per liter of water. Milli-equivalents perliter are calculated by dividing the moles per liter of solute by thenumber of charged species (groups) per molecule of solute, which is thendivided by a factor of 1,000.

A preferred water of the invention is treated in order that it isessentially free of chemical and microbial contamination and at aminimum meets the purity requirements established by the Association forthe Advancement of Medical Instrumentation (AAMI) for dialysatecompositions. The water may also be referred to as treated water orAAMI-quality water. A monograph describing water treatment fordialysate, monitoring of water treatment systems, and regulation ofwater treatment systems is available from AAMI (Standards Collection,Volume 3, Dialysis, Section 3.2 Water Quality for Dialysis, 3 ed., 1998,AAMI, 3330 Washington Boulevard, Arlington, Va. 2220.1). In addition,all of the other components of the dialysate composition of the presentinvention are preferably at least at the level of United StatesPharmacopoeia (USP)-grade purity, which is generally a purity of about95%. The purity of the components is preferably at least about 95%, morepreferably at least about 98%, and more preferably at least about 99%.

In order to facilitate the diffusion between blood and dialysate, it isdesirable to maintain an osmotic gradient between the fluids by addingan osmotic agent to the dialysate. The presence of an osmotic agent inthe peritoneal dialysate will encourage excess fluid and metabolic wastebyproducts to flow from the blood and into the dialysate. A suitableosmotic agent for the dialysate composition is sugar. The sugar ispreferably selected from glucose (e.g., dextrose), poly(glucose) (i.e.,a polymer made from repeating glucose residues, e.g., icodextrin, madefrom repeating dextrose units), or fructose. While it is possible tomake a dialysate with no sugar, if sugar is to be added to the dialysatecomposition, it is generally dextrose. It is further appreciated thatany biocompatible, non-sugar osmotic agent that functions as anequivalent could be a viable substitute. The sugar is typically presentin the acid concentrate in sufficient amounts to provide a concentrationof 0 to 40 g/L on anhydrous basis in the final dialysate. In thepreferred embodiment, glucose (i.e., dextrose monohydrate) is includedin the acid concentrate in solubilized form to circumvent any potentialdissolution problems in preparing the final dialysate formulation.

Table 2 lists the preferred constituents, concentration ranges and ionicstrength for the acid concentrates. In the preferred embodiment of theinvention, the acid concentrate is prepackaged in container, admixedwith the bicarbonate concentrate in a dialysate preparation tank with apredetermined volume of water, then diluted to produce a 54.5 L batchdialysate using a home dialysis system such as the one described in theabove referenced Kenley et al. patent.

TABLE 2 Acid concentrate range Constituent Concentration (g/L) IonicStrength (mEq/L)* NaCl 80-159 10-20 (Na⁺) KCl 0-41 0-4 (K⁺) CaCl₂_(•)2H₂O 0-40 0.00-4.0 (Ca⁺) MgCl₂•6H₂O 7-21 0.5-2.5 (Mg⁺⁺) CH₃COOH 0-370-4.5 (CH₃COO⁻) Dextrose monohydrate  0-376 NA Conductivity Range* 2-3mS/cm NA *when diluted with water in a batch tank to a ratio of 1:135.6

The desired concentration of potassium, calcium and magnesium ions inthe acid concentrate varies from patient to patient. Generally, theamount of potassium chloride is present in an amount ranging betweenabout 0.00 g and about 41 g/L of acid concentrate. The amount of calciumchloride (dehydrate form, CaCl₂.2H₂O) generally ranges between about0.00 and about 40 g/L of acid concentrate. The amount of magnesiumchloride (hexahydrate form, MgCl₂.6H₂O) generally ranges between about 7and about 21 g/L of acid concentrate. At the aforementionedconcentrations, a stable acid concentrate is produced which can beshipped and stored for prolonged periods at a broad range oftemperatures, including temperatures ranging between about −10 to −20 F,without freezing solid or precipitating out.

While the chloride salts of sodium, potassium, calcium and magnesium arepreferred in practicing this invention, it will be understood by thepractitioner that other water soluble physiologically acceptable saltsof sodium, potassium, calcium and magnesium ions may be used to replaceall or part of the corresponding chloride salts. Suitable, butnon-limiting, salts include sulfates, carbonates, phosphates, acetates,lactates, and gluconates. If desired, hydrochloric acid, lactic acid,sodium diacetate or any other suitable acid may also be used to replaceall or part of the acetic acid employed in the acid concentrate.

The bicarbonate base concentrate of the invention includes a dryadmixture of sodium chloride, sodium bicarbonate, and citrate in apredetermined ratio. Table 3 lists the preferred constituents,concentration ranges, and ionic strength for the citrate-containingbicarbonate concentrates. Admixture of the bicarbonate concentrate batchunit with any of the acid concentrate batch units of the invention in anappropriate amount of water will result in a physiologically acceptabledialysate solution.

The base from which base concentrate is almost universally prepared indialysis clinics is sodium bicarbonate, and this is the preferred basein the present compositions and methods. The bicarbonate concentrate ina dialysate is preferably from about 25 to 40 mEq/L. Optionally, thesodium bicarbonate in a base concentrate may be replaced, in part, witha different physiologically-acceptable base. The anionic portion of asuitable replacement for sodium bicarbonate may be, for example,carbonate, lactate, citrate and acetate. Accordingly, the base for abase concentrate may be selected from the salt forms of any ofbicarbonate and, optionally, carbonate, lactate, citrate and acetate.Also present in the salt forms will be one or morephysiologically-acceptable cations selected from sodium, potassium,calcium and magnesium. These salts and acids are electronically neutral,i.e., there are an equal number of negative and positive charges.

As used herein, “citrate” refers to a citrate anion, in any form,including citric acid (citrate anion complexed with three protons),salts containing citrate anion, and partial esters of citrate anion.Citrate anion is an organic tricarboxylate. Citric acid, which has beenassigned Chemical Abstracts Registry No. 77-92-2, has the molecularformula HOC(CO₂H)(CH₂CO₂H)₂ and a formula weight of 192.12 g/mol. Acitrate salt (i.e., a salt containing citrate anion) is composed of oneor more citrate anions in association with one or morephysiologically-acceptable cations. Exemplary physiologically-acceptablecations include, but are not limited to, protons, ammonium cations andmetal cations. Suitable metal cations include, but are not limited to,sodium, potassium, calcium, and magnesium, where sodium and potassiumare preferred, and sodium is more preferred. A composition containingcitrate anion may contain a mixture of physiologically-acceptablecations.

A partial ester of a citrate anion will have one or two, but not allthree, of the carboxylate (i.e., —CO₂ ⁻) groups of citrate anion in anester form (i.e., —COOR, where R is an organic group). In addition toone or two R groups, the partial ester of a citrate anion will includeone or two physiologically-acceptable cations (so that the total of theR group(s) and cation(s) equals three). The R group is an organic group,preferably a lower alkyl.

The citrate is preferably in association with protons and/or metalcations. Exemplary of such citrate compounds are, without limitation,citric acid, sodium dihydrogen citrate, disodium hydrogen citrate,trisodium citrate, trisodium citrate dihydrate, potassium dihydrogencitrate, dipotassium hydrogen citrate, calcium citrate, and magnesiumcitrate. In one embodiment, the citrate is present in the basecomposition in the form of one or more of citric acid, sodium dihydrogencitrate, disodium hydrogen citrate, potassium dihydrogen citrate, ordipotassium hydrogen citrate. In a preferred embodiment, sodium citrateprovides the source for the citrate anions. Sodium citrate may be in theform of a dry chemical powder, crystal, pellet or tablet. Anyphysiologically tolerable form of citric acid or sodium citrate may beused to introduce citrate anions to the bicarbonate composition. Forinstance, the citric acid or sodium citrate may be in the form of ahydrate, including a monohydrate.

Citrate has been previously recognized to be able to function as ananti-coagulant in the bloodstream by binding calcium. It has beensuccessfully used for regional anticoagulation in hemodialysis.Concentration of citrate (up to 1.6 moles/L) are infused on the arterialside before the dialyzer and then additional calcium and magnesium saltsare infused post dialyzer to keep ionized calcium and magnesium balancein the blood stream. Also, citrate concentrations as high as 47 mEq/L,are used in whole blood and plasma collection bags to preserve the bloodfor transfusion and prevent it from clotting. The blood and plasmacollected along with highly concentrated citrate is transfused topatients. Typically, plasma donation introduces 3.2 grams of sodiumcitrate in the donor's blood stream. This amount of citrate metabolizesrapidly in the body and converts to bicarbonate, which is the naturalbuffer in the blood stream. Accordingly, the citrate concentration ofthe bicarbonate concentrate should be selected in view of itsanti-coagulation properties. Unless other measures are taken, thecitrate concentration should not exceed about 8 mEq/L, and is preferablynot more than about 4 mEq/L when diluted in the final dialysatesolution. When citrate concentrations of higher than 8 mEq/L areemployed, the magnesium and/or calcium concentration of the dialysatecomposition must be increased to compensate for calcium and magnesiumions lost to reaction with citrate. This can involve complicatedphysiological balancing of ionized calcium and magnesium such thathigher than 8 mEq/L of citrate is not recommended in the dialysatesolutions.

When sodium citrate is used as the citrate source, the bicarbonateconcentrate may exist as a dry chemical mixture of salts. Since sodiumcitrate does not react with bicarbonate, citrate and bicarbonate saltsdo not need to be physically separated. These salts may be formed intotablets or pellets if desired. If citric acid or disodium citrate isused as the citrate source, the citrate is physically separated from thebicarbonate to avoid chemical reaction. Thus, in one embodiment of theinvention, the bicarbonate base and citrate are physically separated ina vessel using sodium chloride salt as a barrier layer. For instance,the reagents can be layered by adding sodium bicarbonate, followed bysodium chloride and lastly citrate. In one aspect of this embodiment,the citrate may be tabletized or pelletized to reduce the surface areaavailable for contact with bicarbonate.

In another embodiment, the citrate may be placed in a subcontainer andthen the subcontainer is placed in the vessel containing the remainingbicarbonate concentrate constituents. In one aspect of this embodiment,the subcontainer may be porous, e.g., a filter bag, which physicallyseparates the citrate from the bicarbonate but allows water, during themixing process, to enter the subcontainer to dissolve the citrate. Inanother aspect of this embodiment, the subcontainer is non-porous, e.g.,a sealed plastic bag, which is pierced just prior to mixing.

In yet another embodiment, the subcontainer is a compartment within thevessel that is created by the use of a physical barrier such as aplastic or paper membrane. The physical barrier separates the citratefrom the bicarbonate and is ruptured just prior to mixing. For instance,sodium bicarbonate and sodium chloride is added to the vessel and scaledusing a paper or plastic membrane insert. Citrate is then added to thevessel. In another embodiment, the citrate is tableted or pelletized anda discrete number of tablets or pellets is added to the vessel to formthe base concentrate. The citrate tablets or pellets may be coated withan isolation coating, i.e., dextrose or sodium chloride, to shield itfrom contact with the bicarbonate. The citrate may be present as asingle or multiple tablets or pellets. In practicing this invention, itis preferred that the dry base concentrate is prepared with citratepellet(s) or tablet(s) which is separated from the bicarbonate base viaa sodium chloride salt layer.

In another embodiment of the invention, the base concentrate includessufficient amounts of citrate, sodium, chloride and bicarbonate toproduce, in the final dialysate, a citrate concentration ranging fromabout 2.5 to 4 mEq/L; sodium in an amount ranging from about 123 to 127mEq/L; chloride in an amount ranging from about 84 to 89 mEq/L; andbicarbonate in an amount ranging from about 30 to 36.5 mEq/L. See Table3. In one aspect of this embodiment, the base concentrate comprisessufficient amounts of bicarbonate, sodium, chloride and citrate toprovide, in the final dialysate, 36.5 mEq/L of bicarbonate; 127 mEq/L ofsodium; 88 mEq/L of chloride; and 2.5 mEq/L, of citrate. In anotheraspect of this embodiment, the base concentrate comprises sufficientamounts of bicarbonate, sodium, chloride and citrate to provide, in thefinal dialysate, 31.5 mEq/L of bicarbonate; 123 mEq/L of sodium; 89mEq/L of chloride; and 2.5 mEq/L of citrate. In yet another aspect ofthis embodiment, the base concentrate comprises sufficient amounts ofbicarbonate, sodium, chloride and citrate to provide, in the finaldialysate, 36.5 mEq/L of bicarbonate; 123 mEq/L, of sodium; 84 mEq/L ofchloride; and 2.5 mEq/L of citrate. In another aspect of thisembodiment, the base concentrate comprises 35 mEq/L of bicarbonate; 127mEq/L of sodium; 88 mEq/L of chloride; and 4 mEq/L of citrate.

TABLE 3 Citrate-containing bicarbonate powder range Constituent StrengthUnits Sodium (Na⁺) 123-127 (mEq/L)* Bicarbonate (HCO₃ ⁺) 30.0-36.5(mEq/L)* Chloride (Cl⁻) 84-89 (mEq/L)* Citrate (C₆H₄O₇) 2.5-4  (mEq/L)*NaCl 267.5-283.5 Gms per bottle NaHCO₃ 137.4-167.1 Gms per bottle SodiumCitrate  8.7-14.0 Gms per bottle Conductivity Range 10.5-12.7 mS/cm*when diluted in a batch tank with 54.5 liters of water

An embodiment of the present invention for commercially availableproportioning systems (per AAMI RD61:2000) is listed in Table 4 below.The acid and bicarbonate concentrates can be supplied in dry forms.Table 4 below depicts the acid concentrate: bicarbonate concentrate:water ratios for the various proportioning dialysate generating systemsthat are commercially available at present. As an example in table 4below, a citrate concentration of 4 mEq/L, an acetate concentration of 4mEq/L and a bicarbonate concentration of 31 mEq/L can provide a finaltotal base concentration of 39 mEq/L. It should be realized that theseconcentrations will differ greatly when the bicarbonate to citrate molarratio is varied from 50:1 to 15:8 as listed in Table 1(a) above and thatthe ratios for different proportioning machines do vary. The baseconcentrates are generally used within 24 hours after a liquid containerhas been opened or a dry package has been dissolved in water.

TABLE 4 Example of proportioning system compositions Mix Ratio = Symbol*sum g/L of Ratio of for of sodium g/L of g/L of sodium proportioningacid, bicarbonate sodium acetic bicarbonate systems - bicarb in citratein acid in to sodium except and Acid Bicarb base base acid citrate inAksys water concentrate concentrate Water concentrate concentrateconcentrate g/g Square 35 1 1.23 32.77 74.4 9.8 8.4 7.60 Circle 36.83 11.83 34 59.2 6.9 8.8 8.55 Triangle 45 1 1.72 42.28 72.5 9.0 10.8 8.05Diamond 36.1 1 1.1 34 77.0 11.3 8.7 6.82 Aksys 136.6 1 10.0 125.6 40.04.7 32.8 8.54 *Adapted from Association for the Advancement of MedicalInstrumentation (AAMI) RD61: 2000

The present invention relates to the use of citrate as a base, mole formole, in the place of bicarbonate or acetate. Thus, for a patientcurrently requiring 39 mEq/L of bicarbonate along with 4 mEq/L ofacetate in the final dialysate, the patient can be provided instead with35 mEq/L of bicarbonate, 4 mEq/L of citrate and 4 mEq/L of acetate. Inanother embodiment, for example, 33 mEq/L of bicarbonate, 5 mEq/L ofcitrate and 3 mEq/L of acetate can be used. The selection of these baseswill depend on the citrate and acetate tolerances of the patient. Suchtolerances are determined by the treating physician.

In practicing this invention, both the acid concentrate and thebicarbonate concentrate of the invention are preferably in the form ofphysically discrete units suitable as unitary dosages for each dialysissession, each unit containing a predetermined quantity of the variousconstituents such when combined with water results in a batch dialysateformulation having the desired concentrations of constituents. The unitdosage forms are preferably contained in prepackaged scaled unit dosecontainers or vessels such as the one described in the Treu et al. U.S.Pat. No. 5,788,099, issued Aug. 8, 1998, which is incorporated byreference herein in its entirety and can be assembled in kit form forone or more dialysis sessions. The vessels described in the Treu et al.patent are especially designed for patient use and are particularlyadvantageous for use in conjunction with the home dialysis machinedescribed in the above-referenced Kenley et al. patent. However, thepresent dialysate chemical formulation invention is of course applicableto other vessel designs and machines. In an embodiment of the invention,vessels can be prepackaged as a kit that includes a container of a drybase component comprising a citrate, a bicarbonate and a salt; and acontainer of a liquid acid concentrate comprising an acid selected fromthe group consisting of acetic acid, citric acid, sodium diacetatelactic acid or any other acid wherein the addition of base concentrateand acid concentrate to a prescribed volume of water produces a finalvolume of a dialysis solution. A set of instructions for using thecomponents would also be included in the kit.

There are a number of advantages that can be obtained from thedistribution of chemicals in the two concentrate bottles according tothe present invention. First, patient safety is assured in batch orproportioning systems that employ the concentrates of the presentinvention. For instance, the conductivity of the acid concentrate of theinvention generally ranges between about 2-3 mS/cm while the bicarbonateconcentrate of the invention generally ranges about 10.5 to 12.7 mS/cm.The combined conductivity ranges between about 12.5 to 15.7 mS/cm. Iftwo acid concentrate bottles are accidentally mixed, the finalconductivity will be below 12.8. Similarly, accidental mixing of twobicarbonate concentrate bottles will result in a combined conductivitythat exceeds 15.7 mS/cm. In either case, the systems that measureconductivity of a dialysate solution prior to initiation of the dialysisprocedure will not start the dialysis procedure. Also, machines aregenerally designed to compare the actual conductivity with theprescribed one within +/−5%. If the contents of any of the bottle didnot mix in the final dialysate solution, the loss of conductivity willbe indicated and dialysis procedure will also be halted.

Ordinarily, the conductivity level of dialysate solution resulting fromthe mixing of vessels containing the acid and bicarbonate concentratesin the batch tank proportioning system would fall within the expectedaforementioned range. No safety alarm will sound and the dialysissession would proceed uneventfully. Inadvertent mixing of two likevessels, e.g., two acid concentrate vessels or two bicarbonateconcentrate vessels, in a system, however, would result in aconductivity that is above or below the expected range and thustriggering the alarm and preventing initiation of the dialysis session

Second, the distribution of the chemicals in the acid and bicarbonateconcentrates of the invention results in a minimum total volume andweight of concentrates per given volume of final dialysate compared withcurrent commercial packages available. Conventional dialysis systemssuch as the ones produced by Baxter and Fresenius generally require 3.43liters of acid and 6.23 liters of bicarbonate concentrate for one 4-hourdialysis treatment. Since a daily dialysis session is typically 90minutes, conventional system volumes required for daily dialysis are1.29 and 2.34 liters, respectively. In contrast, the present inventioncan provide a total concentrate volume of as little as 0.9 liters (2×450mL bottle) versus a conventional system of 3.63 liters (1.29 L+2.34 L).In other words, the acid and bicarbonate concentrates of the inventionare about 4 (3.63/0.9) times more compact in terms of volume compared toconventional systems. Moreover, the nearly saturated acid concentrateprovides protection against freezing and dextrose recrystallization, acommon problem found in conventional acid concentrate formulations.

Third, the distribution of the chemicals in the acid and bicarbonateconcentrates of the invention results in greater control and accuracy ofsodium and chloride ion concentrations in the dialysate. One of theproblems with the conventional systems is maintaining high levelaccuracy of sodium and chloride ions. Many physicians prefer +/−2% forthese ions. ANSI/AAMI RD-61:2000 standards recommends less than 2.5%variation for sodium. Since the conventional systems involve making aconcentrate for sodium bicarbonate (with or without sodium chloride) andthen subsequently dilute to final volume, high accuracy cannot beobtained. The concentrate formulations of the present invention aredesigned to have only small portions of sodium chloride in acidconcentrate and have all the rest of the sodium in powder from which isdiluted directly. By shifting most of the sodium ions to dry powder, itis now possible to achieve +/−1% accuracy of 90% of sodium chloride and100% of sodium bicarbonate in the dialysate. Moreover, it is easy tocontrol weights of dry powder components in the concentrate (+/−1%)formulations, thus allowing much higher degree of accuracy in the finalsolution.

Fourth, both the acid and bicarbonate concentrates of the inventionoccupy nearly equal volumes and this advantageously allows for identicalcontainer design, thus reducing costs of molds and manufacturingprocesses. Furthermore, identical container design makes it easier forthe manufacturer as well as for the user. Since the connection to themachines are identical and mix-up eliminated by color coding, visuallabel checking and conductivity assurance, the use of the acid andbicarbonate concentrates of the invention to prepare batch dialysateprovide the highest degree of quality assurance and safety to thepatients.

Finally, by providing citrate ion in the powder form with drybicarbonate base powder, a number of advantages can be had such as: (1)high accuracy for citrate and sodium ions can be achieved, (2) longershelf-life for powder will be possible compared with a dissolved citrateion in acid formulation, (3) possible to use current standard acidconcentrate formulations for citrate dialysis, (4) reduce number ofadditional liquid codes required, and (5) allow simple manufacturingoperation for citrate based dialysis formulations.

In the examples below, a procedure is described using a home dialysismachine for preparing a batch dialysate and for preparing a dialysateusing a proportioning system. Tables are also provided which listrepresentative acid and bicarbonate concentrate formulations as well asbatch dialysate formulations prepared by various combinations of the twoconcentrates. The selection of a particular combination of acidconcentrate and bicarbonate concentrate to prepare a 54.5 L batch of adialysate formulation having a desired balance of electrolytes islargely dependent on the patient's condition and health needs, and willbe prescribed by a physician. The resulting batch of dialysate preparedby mixing the two components in water and diluting the solution to 54.5L does not require any further manipulations such as pH adjustment. Theconcentrate containers are designed to provide chemicals for batchvolumes ranging from 40 liters to 60 liters. The concentrate containerscan also be designed to provide continuous streams of acid and baseconcentrates containing citrate to a proportioning system and tomultiple treatment delivery systems.

Example 1 Preparation of Batch Dialysate

All chemical reagents employed in preparing the concentrates are USPgrade unless otherwise indicated.

(a) Preparation of Batch Quantity Acid Concentrate Unit.

In making the acid concentrate, dextrose is dissolved in a predeterminedamount of water with continuous stirring at room temperature, e.g. 70°F. Thereafter, the remaining salts and acetic acid are slowly added tothe stirring of the solution and the solution volume is raised to afinal volume, e.g., 399 mL, with appropriate amounts of water to producethe acid concentrate. If desired, the concentrate may be sterilized byfiltration through a sterile 0.2 micron filter or by autoclaving. Theacid concentrate is then poured into a batch quantity vessel such as theone described in the above-referenced Treu et al. patent, and the vesselsealed.

(b) Preparation of Batch Quantity Dry Bicarbonate Unit.

In making the dry bicarbonate concentrate, 280.3 grams of NaCl, and160.2 grams of NaHCO₃, are thoroughly mixed with 14 grams of sodiumcitrate. The resulting 454.4 gram powder mixture is then placed into abatch quantity vessel such as the one described in the above-referencedTreu et al. patent, and the vessel scaled. Alternatively, the salts aresimply added to the batch quantity vessel and sealed. No additionalmixing in the vessel is required because all of them are completelydissolved in the dialysate tank and thus uniformly distributed.

(c) Preparation of Batch Dialysate.

A 54.5 liter dialysate chemical solution tank is installed in a dialysismachine. The tank has a chemical loading platform that acts as a meansfor receiving the dialysate chemicals and for introducing the chemicalsinto the tank. The tank is filled up to the level of the chemicalloading platform, or roughly 50 percent of capacity. The chemicalloading platform has a slanted shelf which is in fluid communicationwith the interior of the tank. The contents of the vessels containingthe batch quantity dry bicarbonate chemicals and the batch quantityliquid acid concentrate are gradually released from the vessels bygravity and are deposited onto the slanted shelf of the loadingplatform. The vessels can be either manually opened or automaticallyopened (in the manner described in the above-referenced Treu et al.patent), depending on the construction of the tank and loading platform.A nozzle sprays reverse-osmosis filtered water onto the slanted shelf todisperse the chemicals into the interior of the tank. The tank is thenfilled completely with RO water. The solution is mixed by swirling thefluid in the tank, accomplished by introducing the RO water into thebottom of the tank generally parallel to the side of the tank, and bywithdrawing solution from the bottom of the tank and reintroducing it atthe top of the tank in a turbulent manner with a sprayer.

The flow path of the dialysate when it is withdrawn from the bottom ofthe tank and reintroduced at the top of the tank includes a conductivitysensor. The conductivity sensor sends conductivity readings to a centralprocessing unit controlling the operation of the machine. When theconductivity readings meet an expected value for the particulardialysate formulation, the solution is deemed mixed and the mixingprocess ceases. The dialysis session then commences according to wellknown techniques.

Table 5 lists representative formulation ranges for different liquidacid concentrates. The particular formulation to be used for preparationof a batch of dialysate depends upon the medical condition of thepatient, and will be prescribed by a physician. The conductivity of acidconcentrate when diluted to the required volume by itself (withoutpowder) will range between 2-3 mS/cm.

Table 6 shows representative formulation ranges for different batchquantity dry bicarbonate chemicals formulations. The dialysate solutionis prepared by mixing one of the formulations from Table 5 with one ofthe formulations from Table 6. As was the case with Table 5, theparticular formulation to be selected from Table 6 depends on themedical condition of the patient, and will be prescribed by thepatient's physician. This formulation is for dilution to a 54.5 literbatch of dialysate. Again, the precise quantities of the salt andbicarbonate may vary depending on the final volume of dialysate that isprepared.

Since there are 16 representative acid concentrate formulations and 6representative bicarbonate formulations, there are 96 possible finaldialysate combinations.

Example 2 Preparation of Concentrates for a Proportioning System

All chemical reagents employed in preparing concentrates are USP gradeunless otherwise indicated.

(a) Preparation of Bulk Quantities of an Acid Concentrate.

This is generally done in a large vessel (50 liters to 25,000 liters).In making an acid concentrate, dextrose is dissolved in a predeterminedamount of water with continuous stirring at room temperature, e.g. 70°F. Thereafter, the remaining salts and acetic acid are slowly addedwhile the mixture is stirred. The mixture is raised to a final chosenvolume with an appropriate amount of water to produce the acidconcentrate. If desired, the concentrate so obtained can be sterilizedby filtration through a sterile 0.2 micron filter or by autoclaving. Theacid concentrate is then transferred into filling machines and filledinto a batch quantity vessel that is commercially available (startingfrom 100 mL container to 55 gallon drum). The containers are then sealedand transported to customers.

(b) Preparation of Batch Quantities of a Dry Bicarbonate Concentrate.

In making a bulk dry bicarbonate concentrate, appropriate quantities ofNaCl, NaHCO₃ and sodium citrate are metered into containers or bags ofappropriate sizes. The user is required to transfer the whole contentsof the dry chemicals into a mixing vessel before use and completelydissolve the chemicals. Alternately, the manufacturer can package theconcentrates in a way similar to how the bulk acid concentrates arepackaged as described in section (a) above.

(c) Final Dialysate Generation.

In case of a proportioning system, the acid concentrate and thebicarbonate concentrate are supplied, to the dialysis machine inready-to-dispense containers (either supplied by the concentratemanufacturer or by the machine manufacturers) along with a water supply.Generally, the dialysis machine has the capacity to adjust appropriatelyto arrive at a correct proportioning ratio so that a desirable finaldialysate is produced.

The examples described above are by way of illustration and are notmeant to limit the scope of the present invention. It is expected thatcertain changes, substitutions and modifications of the presentinvention will be apparent to a person skilled in the art to which thepresent invention pertains, without departing from the spirit of thepresent invention.

TABLE 5 Formulation table for batch quantity acid concentrate Acid “A”codes - Acid formulations for “Citrate Containing Base” FormulationsmEq/l mEq/l mEq/l mEq/l mg/dl mEq/l mEq/l Acid Code Na+ K+ Ca++ Mg++Dextrose Acetate− Cl− 1A01 15 3 3.0 0.75 200 4 21.75 1A02 15 3 2.5 0.75200 4 21.25 1A03 15 2 3.0 0.75 200 4 20.75 1A04 15 2 2.5 0.75 200 420.25 1A05 15 3 3.5 0.75 200 4 22.25 1A06 15 2 2.5 1.50 200 4 21.00 1A0715 3 3.5 1.00 200 4 22.50 1A08 15 2 3.5 0.75 200 4 21.25 1A09 15 1 2.51.00 200 4 20.50 1A10 15 2 0.0 1.00 200 4 18.00 1A11 15 2 3.0 1.00 200 421.00 1A12 15 2 3.0 1.00 0 4 21.00 1A13 15 2 2.5 1.00 0 4 20.50 1A14 151 2.5 1.00 200 4 19.50 1A15 15 1 3.0 0.75 200 4 19.75 1A16 15 0 2.5 0.75200 4 18.25

TABLE 6 Formulation table for batch quantity citrate-containingbicarbonate concentrate Total Base Sodium Sodium Sodium with Citrate-Chloride Bicarbonate Citrate Total Bicarbonate Sodium Chloride CitrateCitrate & Containing NaCl NaHCO₃ C₆H₅Na₃O₇ Weight HCO₃ Na Cl C₆H₄O₇Acetate Code # Gms gms Gms gms mEq/L mEq/L mEq/L mEq/L mEq/L 1B11 280.3167.1 8.7 456.1 36.5 127 88 2.5 39 1B12 283.5 144.2 8.7 436.4 31.5 12389 2.5 34 1B13 267.5 167.1 8.7 443.4 36.5 123 84 2.5 39 1B14 280.3 160.214.0 454.5 35.0 127 88 4 39 1B15 283.5 137.4 14.0 434.8 30.0 123 89 4 341B16 267.5 160.2 14.0 441.7 35.0 123 84 4 39 Note: The quantities in gmsrepresent typical formulations for use with a batch system of 54.5liters final volume. These weights will be proportionately more or lessfor different batch volumes and for proportioning system.

1-76. (canceled)
 77. A method of making a dialysate and circulating thedialysate comprising: (a) mixing a base concentrate, an acidconcentrate, and water so as to produce dialysate, said base concentratecomprising a citrate, bicarbonate and a salt, wherein a sodiumcontribution of said base concentrate to the dialysate ranges from 100to 150 mEq/L and said acid concentrate comprising an acid selected fromthe group consisting of acetic acid, citric acid and lactic acid,wherein (i) a sodium contribution of said acid concentrate to thedialysate ranges from 10 to 20 mEq/L, (ii) the combination of the sodiumcontributions of said base concentrate and said acid concentrate to thedialysate ranges from 125 to 150 mEq/L; (b) measuring conductivity ofsaid dialysate with a conductivity sensor; and (c) circulating saiddialysate to a dialysate side of a dialyzer if said conductivity of saiddialysate ranges from between about 12.5 and about 15.7 mS/cm and notcirculating the dialysate if said conductivity falls outside of saidconductivity range.
 78. The method of claim 77, wherein said citrate isselected from the group consisting of citric acid, a salt of citricanion, and a partial ester of citric anion.
 79. The method of claim 77,wherein said citrate is trisodium citrate, disodium hydrogen citrate ormonosodium dihydrogen citrate.
 80. The method of claim 77, wherein saidacid in said acid concentrate is acetic acid.
 81. The method of claim77, wherein said salt is selected from the group consisting of sodiumchloride, potassium chloride, calcium chloride and magnesium chloride.82. The method of claim 77, wherein said citrate is provided in aquantity to provide a concentration from about 1 to about 8 mEq/L insaid dialysate.
 83. The method of claim 77, wherein said bicarbonate isprovided in a quantity to provide a concentration from about 15 to about50 mEq/L in said dialysate.
 84. The method of claim 77, wherein saidsalt is provided in a quantity to provide a concentration from about 1.5to about 150 mEq/L in said dialysate.
 85. The method of claim 77,wherein said acid in said acid concentrate being provided in a quantitysufficient to provide a concentration from about 1 to about 8 mEq/L insaid dialysate.
 86. The method of claim 77, wherein the base concentratecomprises: (a) sodium bicarbonate; (b) sodium citrate, wherein molarratio of sodium bicarbonate to sodium citrate ranges from 50:1 to 15:9;and (c) sodium chloride in an amount sufficient to provide aconcentration of sodium in the range of 125 to 150 mEq/L when the baseconcentrate and acid concentrate are mixed with water.
 87. The method ofclaim 77, wherein the base concentrate comprises: (a) bicarbonate insufficient amount to provide about 36.5 mEq/L in said dialysate; (b)sodium in sufficient amount to provide about 127 mEq/L in saiddialysate; (c) chloride in sufficient amount to provide about 88 mEq/Lin said dialysate; and (d) citrate in sufficient amount to provide about2.5 mEq/L in said dialysate.
 88. The method of claim 77, wherein thebase concentrate comprises: (a) bicarbonate in sufficient amount toprovide about 31.5 mEq/L in said dialysate; (b) sodium in sufficientamount to provide about 123 mEq/L in said dialysate; (c) chloride insufficient amount to provide about 89 mEq/L in said dialysate; and (d)citrate in sufficient amount to provide about 2.5 mEq/L in saiddialysate.
 89. The method of claim 77, wherein the base concentratecomprises: (a) bicarbonate in sufficient amount to provide about 36.5mEq/L in said dialysate; (b) sodium in sufficient amount to provideabout 123 mEq/L in said dialysate; (c) chloride in sufficient amount toprovide about 84 mEq/L in said dialysate; and (d) citrate in sufficientamount to provide about 2.5 mEq/L in said dialysate.
 90. The method ofclaim 77, wherein the base concentrate comprises: (a) bicarbonate insufficient amount to provide about 35 mEq/L in said dialysate; (b)sodium in sufficient amount to provide about 127 mEq/L in saiddialysate; (c) chloride in sufficient amount to provide about 88 mEq/Lin said dialysate; and (d) citrate in sufficient amount to provide about4 mEq/L in said dialysate.
 91. The method of claim 77, wherein the baseconcentrate comprises: (a) bicarbonate in sufficient amount to provideabout 30.0 mEq/L in said dialysate; (b) sodium in sufficient amount toprovide about 123 mEq/L in said dialysate; (c) chloride in sufficientamount to provide about 89 mEq/L in said dialysate; and (d) citrate insufficient amount to provide about 4 mEq/L in said dialysate.
 92. Themethod of claim 77, wherein the base concentrate comprises: (a)bicarbonate in sufficient amount to provide about 35 mEq/L in saiddialysate; (b) sodium in sufficient amount to provide about 123 mEq/L insaid dialysate; (c) chloride in sufficient amount to provide about 84mEq/L in said dialysate; and (d) citrate in sufficient amount to provideabout 4 mEq/L in said dialysate.
 93. The method of claim 77, whereinprior to step (a), the base concentrate and acid concentrate areseparately dissolved into water to form aqueous base and acidconcentrates.
 94. The method of claim 92, wherein the aqueous base andacid concentrates are metered to a metered volume of water so as toproduce said dialysis solution on-line on a continuous basis.
 95. Thesystem of claim 77, wherein the dialyzer is part of a fixed-volumedialysis proportioning system.
 96. The system of claim 77, wherein thedialyzer is part of a dynamic dialysis proportioning system.
 97. Thesystem of claim 77, wherein the ratio of bicarbonate (mEq/L) to citrate(mEq/L) in the base concentrate ranges from 50:1 to 15:8.